Porous inorganic solids have found great utility as catalysts and separations media for industrial application. The openness of their microstructure allows molecules access to the relatively large surface areas of these materials that enhance their catalytic and sorptive activity. The porous materials in use today can be sorted into three broad categories using the details of their microstructure as a basis for classification. These categories are the amorphous and paracrystalline supports, the crystalline molecular sieves and modified layered materials. The detailed differences in the microstructures of these materials manifest themselves as important differences in the catalytic and sorptive behavior of the materials, as well as in differences in various observable properties used to characterize them, such as their surface area, the sizes of pores and the variability in those sizes, the presence or absence of X-ray diffraction patterns and the details in such patterns, and the appearance of the materials when their microstructure is studied by transmission electron microscopy and electron diffraction methods.
Amorphous and paracrystalline materials represent an important class of porous inorganic solids that have been used for many years in industrial applications. Typical examples of these materials are the amorphous silica's commonly used in catalyst formulations and the paracrystalline transitional aluminas used as solid acid catalysts and petroleum reforming catalyst supports. The term “amorphous” is used herein to indicate a material with no long-range order, although almost all materials are crystalline to some degree, at least on the local scale. An alternate term that has been used to describe these materials is “X-ray indifferent”. The microstructure of silica's consists of 10 to 25 nm particles of dense amorphous silica, with porosity resulting from voids between the particles. Since there is no long-range order in these materials, the pore sizes tend to be distributed over a rather large range. This lack of order also manifests itself in the X-ray diffraction pattern, which is usually featureless.
Paracrystalline materials such as the transitional aluminas also have a wide distribution of pore sizes, but have better defined X-ray diffraction patterns usually consisting of a few broad peaks. The microstructure of these materials consists of tiny crystalline regions of condensed alumina phases and the porosity of the materials results from irregular voids between these regions. Since, in the case of either material, there is no long-range order controlling the sizes of pores in the material, the variability in pore size is typically quite high. The sizes of pores in these materials fall into a regime called the mesoporous range, which is from about 1.3 nm to about 20 nm.
Generally, porous substances are divided by pore size, for example, pore sizes smaller than 2 nm classified as microporous substances, between 2 and 50 nm classified as mesoporous substances and larger than 50 nm classified as macroporous substances. Of the porous substances, those having uniform channel, such as zeolite, are defined as molecular sieves and up to hundreds of types of species have been found and synthesized thus far. Zeolites play an important role as catalysts or carriers in modern chemical industries by virtue of their characteristics including selective adsorptivity, acidity and ion exchangeability.
U.S. Pat. No. 6,630,170 discloses a mesoporous composition prepared from a mixture comprising hydrochloric acid, vitamin E and a silica source, wherein said vitamin E functions as a templating molecule, and said mesoporous composition exhibits uniform pore size.
Another difficult problem for the pharmaceutical industry is the formulation of drugs having low or very low water-solubility into solid dosage forms, especially formulations intended for immediate release. Few solutions to this problem have been disclosed in the art. For instance, US 2001/0048946A provides solid dosage forms of sparingly water-soluble pharmaceutical agents, i.e. solid or crystalline drugs having a water-solubility of 10 to 33 μg/mL at 25° C., such as glitazones. More particularly, this document discloses a pharmaceutical composition in the form of a solid particulate dispersion of such a pharmaceutical agent dispersed throughout a matrix of a water-soluble polymer such as polyvinylpyrrolidone, hydroxy-propyl cellulose, or hydroxypropyl methylcellulose. In a preferred embodiment, the particulate pharmaceutical agent is dispersed in the water-soluble polymer in a weight ratio of about 10% to about 90% active ingredient to about 90% to about 10% polymer. Other conventional excipients such as glycerin, propyleneglycol, Tween, stearic acid salts and the like can be added.
US 2001/0044409A discloses a process for the preparation of a poorly water soluble drug in solid dispersion comprising the steps of (a) blending the drug with a carrier, (b) dissolving a surfactant and a plasticizer/solubilizer in water, (c) spraying the surfactant-plasticizer/solubilizer solution onto the drug/carrier mixture in a fluid bed granulator, (d) extruding the resulting granulation through a twin screw extruder with at least one heating zone, and (e) milling the extrudate to a powdery mass of the solid drug dispersion. Within this process, the carrier may be selected from the group consisting of polyvinylpyrrolidone, high molecular weight polyethylene glycol, urea, citric acid, vinyl acetate copolymer, acrylic polymers, succinic acid, sugars and mixtures thereof; the plasticizer/solubilizer may be selected from the group consisting of low molecular weight polyethylene glycol, propylene glycol, glycerin, triacetin, triethyl citrate, sugar alcohols and mixtures thereof, and the said surfactant may be selected from the group consisting of Tween, Span, Pluronics, polyoxyethylene sorbitol esters, monodiglycerides, polyoxy-ethylene acid polyoxyethylene alcohol and mixtures thereof. This process suffers from the disadvantage of providing a heating zone in the twin-screw extruder and consequently controlling and monitoring the temperature profile of the extruder.
However, none of the above processes appear to be successful in formulating solid dosage forms of drugs having very low water-solubility, i.e. a solubility lower than 10 μg/mL, preferably lower than 5 μg/mL. This problem is applicable to a large number of drugs, including those belonging to the family of diaminopyrimidines, such as stated in U.S. Pat. No. 6,211,185.
U.S. Pat. No. 3,639,637 discloses oestrogen compositions for the preparation of stable aqueous suspensions that can be sprayed onto animal feed, comprising (by weight) 70-95% of water-dispersible gel-forming microcrystalline cellulose and 5-30% of finely-divided diethylstilbestrol (a compound which is virtually insoluble in water) and optionally further up to one third of the weight of the composition of a hydrocolloid selected from the group consisting of sodium carboxy-methylcellulose, methylcellulose and hydroxyethylcellulose. The two latter cellulose compounds are known, namely from EP-A-403 383, to contribute to an extended linear drug release rate.
WO-A-99/12524 solves the problem of drug formulations with both a relatively fast or quick onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time, by providing an oral modified release multiple-units composition wherein the unit dosage form comprises at least (i) a first fraction being able to release at least 50% of the drug within the first 20 minutes of a certain dissolution method, and (ii) a second fraction for delayed and extended release of the drug. The multiple-units of the first fraction may be granulates or, provided that a surfactant is added to the formulation, coated or uncoated pellets. Formulation of the first fraction depends on the specific drug but typically includes wet-granulation, and an antacid-like or other alkaline substance was found to have a pronounced increasing effect on the release rate.
U.S. Pat. No. 5,646,131 discloses (example 4) rapidly dissolving capsules containing a granulate formulation of a water-insoluble or sparingly soluble drug, such as terfenadine (less than 0.01 mg/mL water-solubility), surfactants (Tween 80 and sodium lauryl sulfate), cyclodextrin, Avicel PH 101 (microcrystalline cellulose) and a disintegrant/swelling agent (Primojel®, i.e. sodium carboxymethyl starch) in a weight ratio of 10:72 to Avicel. These capsules provide better drug absorption, due to the presence of cyclodextrin, as evidenced by the figure showing a 90% drug release within 45 minutes.
U.S. Pat. No. 4,235,892 discloses a series of 1-aryl-2-acylamido-3-fluoro-1-propanol antibacterial agents including D-(threo)-1-p-methylsulfonyl phenyl-2-dichloroacetamido-3-fluoro-1-propanol, an antibacterial agent known as florfenicol and useful for veterinary purposes. Florfenicol has low solubility in water (about 1.3 mg/mL), as well as in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, and benzyl alcohol. For oral administration, these 1-aryl-2-acylamido-3-fluoro-1-propanol may be compounded in the form of tablets, or may even be admixed with animal feed. U.S. Pat. No. 4,235,892 therefore discloses making tablets by compressing granules of a composition comprising the said 1-aryl-2-acylamido-3-fluoro-1-propanol (in a drug loading range from 8.3% to 41.7% by weight), lactose, microcrystalline cellulose, starch and magnesium stearate.
The Biopharmaceutical Classification System (hereinafter referred as BCS) according to G. Amidon et al. in Pharm. Res. (1995) 12:413-420 provides for two classes of poorly soluble drugs, i.e. Class II and Class IV, and a class of highly soluble drugs, i.e. Class I. According to M. Martinez et al., Applying the Biopharmaceutical Classification System to Veterinary Pharmaceutical Products (Part I: Biopharmaceutics and Formulation Consideration) in Advanced Drug Delivery Reviews (2002) 54:805-824, a drug substance should be classified as highly soluble when the highest dose strength is soluble in at most 250 mL of aqueous media over the pH range 1-7.5. In view of its water solubility (1.3 mg/mL) and of a maximal dose of 20 mg/kg for pigs, it is easy to calculate that the highest dose strength of florfenicol administered to pigs is soluble in an amount of water, which is well above the limit value for the definition of a class I BCS highly soluble drug. Furthermore it is known from J. Voorspoels et al. in The Veterinary Record (October 1999) that florfenicol has a good oral bioavailability, so that it can be classified as a Class II compound as it is not a highly soluble drug and it shows no absorption problems.
There is a specific need in the art to provide a solid formulation of drugs with a water-solubility like florfenicol or lower. Florfenicol is a drug for oral administration to warm-blooded animals, such as cattle with naturally-occurring bovine respiratory disease, swine, sheep, goats and poultry, which at present is only available in the form of injectable solutions. Until now the skilled person has failed in the design of such a solid formulation of florfenicol, which can further be admixed with animal feed if necessary. Also there is a need for a solid formulation for low solubility drugs for human therapies.
Previous data demonstrate that in the case of drugs that are (weak) bases, the ability to create supersaturated solutions depends on gastric acidity. In the case of physiological malfunctions associated with hypochlorhydria or achlorhydria, however, the condition of an initial acidic environment to dissolve basic drugs is not fulfilled. Achlorhydria and hypochlorhydria refer to a disorder in which the production of gastric acid in the stomach is absent or low, respectively. Relying merely on the gastrointestinal acid-base sequence for enhancing bioactivity thus holds the risk of uncontrolled precipitation of the drug compound at the site of absorption.
These conditions are associated with various other medical problems, which also need treatment. The decreased acid level itself causes few symptoms, but low acid levels in the stomach are linked with bacterial overgrowth (as the stomach does not kill microbes normally present in food), which can manifest itself as diarrhea or decreased absorption of nutrients or vitamins. Risk of particular infections, such as Vibrio vulnificus (commonly from seafood) is increased. These infections may need specific drug treatments with the drug needing to dissolve in a non-acidic environment or in the presence of an abnormally small amount of hydrochloric acid.
There are several underlying causes for achlorhydria or hypochlorhydria such as: autoimmune disorders where there is antibody production against parietal cells, which normally produce gastric acid; a symptom of rare diseases such as mucolipidosis (type IV).
A symptom of Helicobacter pylori infection which neutralizes and decreases secretion of gastric acid to aid its survival in the stomach; a symptom of pernicious anemia, atrophic gastritis, VIPomas or of stomach cancer or adiation therapy involving the stomach. These conditions may need specific treatment by drugs that have to dissolve in a non-acidic environment or of presence of an abnormally small amount of hydrochloric acid.
Other conditions of decreased acidity in the stomach can, for instance, often be observed in HIV infected patients; therefore significant effects on the oral bioavailability of poorly water soluble compounds and on the success of the formulation strategy mentioned before can be expected.
The same hurdle is encountered in 10 to 20% of elderly people as they exhibit either diminished (hypochlorhydria) or no gastric acid secretion (achlorhydria), leading to basal gastric pH values >5.0. Such patient group are thus in need of oral medicated treatments by dosage form that allow various classes of drug entities for the treatment for various disorders to dissolve in non-acidic environment or of presence of an abnormally small amount of hydrochloric acid.
An example of the problems related to gastric pH is, for instance, a recent study on the direct influence of gastric pH on atazanavir absorption. When lansoprazole, a proton pump inhibitor, was co-administered with atazanavir, a drastic reduction in bioavailability of atazanavir was observed.
Similar behavior was also reported for the bead-based capsules of Sporanox® which exhibit a significantly lower oral bioavailability of itraconazole when dosed to human subjects suffering from a reduced acidity of the stomach. This indicates that the co-dissolving HPMC phase cannot enhance the extent of absorption when hypochlorhydria is involved. It is therefore often recommended to co-administer an acidic soda beverage in patients who use the capsule formulation of itraconazole.
Similar problems, yet unsolved in a suitable manner, arise with a growing number of therapeutic drugs with poor solubility like for instance itraconazole and diazepam. Solving such problems constitutes another goal of the present invention.